Regional delivery of therapeutic agents for the treatment of vascular diseases

ABSTRACT

The present invention relates to the regional delivery of therapeutic agents for the treatment of vascular diseases wherein regional delivery refers to delivery of a therapeutically effective amount of the therapeutic agent to an area of the vessel that includes not only afflicted tissue but non-afflicted tissue at the periphery of the afflicted tissue as well.

FIELD

The present invention relates to the regional treatment of vasculardiseases.

BACKGROUND

The traditional methods of administering therapeutic agents for thetreatment of various diseases have been either systemic or local.Systemic delivery involves the administration of a therapeutic agent ata discrete location followed by the dispersal of the agent throughoutthe patient's body including, of course, to the target treatment site ororgan. In order to achieve a therapeutically effective amount of theagent at the afflicted site, it is usually necessary to administer aninitial dose substantially greater than the therapeutically effectiveamount to account for the dilution the agent undergoes as it travelsthrough the body. Systemic delivery is carried out primarily in twoways: introduction of the therapeutic agent into the digestive tract(enteral administration) or into the vascular system (parenteraladministration), either directly such as injection into a vein or anartery or indirectly such as injection into a muscle or into the bonemarrow. Delivery by each of these routes is strongly influenced by theso-called ADMET factors: absorption, distribution, metabolism, excretionand toxicity. For enteric administration, such factors as a compound'ssolubility, its stability in the acidic environs of the stomach and itsability to permeate the intestinal wall all affect the extent to whichthe drug is absorbed and therefore its bioavailability. For parenteraldelivery factors such as enzymatic degradation, thelipophilic/hydrophilic partitioning coefficient, protein binding, etc.will affect the bioavailability of an agent.

Local delivery comprises administration of the therapeutic agentdirectly to the target site. The ADMET factors tend to be less importantthan with systemic administration since the agent is being administeredessentially directly to the treatment site. Thus, the initial dose canbe at or very close to the therapeutically effective amount. With time,some of the locally delivered therapeutic agent may diffuse over a widerregion but such is not the intent of localized delivery and theconcentration of the diffused agent will ordinarily be sub-therapeutic,i.e., too low to have a therapeutic effect. Since localized deliverytargets only the desired treatment site, it is possible that some of thecausal factors of the disease that have spread to as yet non-afflictedregions of the organ at the periphery of the afflicted region may notundergo sufficient treatment, resulting in reoccurrence of the disease.

What would be beneficial are devices and methods that can be used totreat a vascular disease such that the ADMET factors are of reducedsignificance as in the case of local delivery while at the same timesome of the broad coverage afforded by systemic delivery is maintained.The current invention provides such devices and methods.

SUMMARY

The present invention provides devices and compositions for and methodsof treating vascular disease by the application of therapeutic agents ina “regional” as opposed to “systemic” or “local” manner. In particular,the method comprises providing a device having a regional deliveryinterface comprising a therapeutic agent, contacting the entire length,or two or more portions of, the delivery interface with a surface of asegment of a vessel that is known or suspected to include a regionafflicted with a vascular disease and delivering the therapeutic agentonto or into the surface of the vessel from the portions of the deliveryinterface in contact with the vessel surface. According to the presentinvention, the portion or portions of the delivery interface in contactwith the surface include not only the known or suspected afflictedregion but a portion of the non-afflicted region at the periphery of theafflicted region.

In contrast to systemic and localized delivery, regional delivery, asused herein, refers to the simultaneous delivery of a therapeuticallyeffective amount of a therapeutic agent to a region of the body, whichextends beyond the actual afflicted site. That is, the regional deliveryof this invention delivers a therapeutic amount of an agent not only tothe specific location known or suspected to be afflicted with a vasculardisease but also delivers a therapeutic amount to adjoiningnon-afflicted tissue. In this manner, sub-clinical causal factorsrelated to the disease may be prevented from developing into clinicalsymptoms after cessation of treatment.

As with local delivery, ADMET is of reduced importance to the regionaldelivery method of this invention compared to systemic delivery and theinitial dose of the therapeutic agent can be closer to the desiredtherapeutic amount. According to one embodiment of this invention, atherapeutic agent is delivered in therapeutically effective amountssimultaneously and in substantially uniform dose to a segment of avessel, wherein the segment is at least about 40 mm in length. Anothernon-limiting example of regional delivery would be to apply a fabricmesh wrap, impregnated with a therapeutic agent, around at least aportion of a vessel or an organ such that the agent is simultaneouslydelivered in therapeutic amounts over substantially the entire contactsurface of the wrap with the vessel or organ.

In an embodiment of the present invention, a device is provided thatcomprises a regional delivery interface capable of administering atherapeutically effective amount of a therapeutic agent to a segment ofa vessel that contains within it a region afflicted with or suspected ofbeing afflicted (hereinafter it is understood that referral to an“afflicted region” refers to both a regions known to be afflicted, aregion suspected to be afflicted and/or to a region that is neitherknown nor suspected to be afflicted but is known or suspected to beparticularly susceptible to affliction, i.e., the device and method ofthis invention may be administered prophylactically) with a vasculardisease and a non-afflicted region at the periphery of the afflictedregion. Preferably at present, the regional delivery interface isgreater than about 40 mm, more particularly between about 40 mm andabout 200 mm and more particularly still, between 40 mm and 100 mm inlength. The regional delivery interface comprises a therapeutic agentwherein one or more portions of the therapeutic agent-containingdelivery interface is/are contacted with a surface of a segment of avessel that includes both afflicted and non-afflicted regions. Thetherapeutic agent is then delivered onto or into the surface of thevessel from the portions of the delivery interface in contact with thevessel surface. According to the invention, if two or more portions ofthe delivery device are contacted with a surface or a segment of asurface of a vessel, the most distant from one another of the two ormore portions contact the surface of the vessel at least in part in thenon-afflicted region of the vessel at the periphery of the afflictedregion.

When the delivery interface comprises a single structure portions ofwhich contact the vessel surface and some of which do not as in thecase, without limitation, of a balloon with multiple diameters wheninflated such that some portions of the balloon contact the vesselsurface and some do not (q.v., below), it is an embodiment of thisinvention that a therapeutic agent may be delivered from thenon-contacting portions of the delivery interface into the space definedby the contacting portions of the delivery interface.

According to an embodiment of the present invention, the therapeuticagent can be administered as a solution in a suitable solvent or as asuspension in a non-solvent carrier using an appropriate deliveryinterface as described hereinafter. Excipients, i.e., inert materialsadded to a drug formulation usually to provide stability, bulk and/or adosage form, can be added if desired.

In another embodiment of the present invention, the therapeutic agentcan be formulated as an emulsion, which may be, without limitation, ananoemulsion.

In a still further embodiment, the therapeutic agent can be incorporatedinto a carrier such as a micelle, a worm micelle, a liposome, apolymerosome, a microparticle or a nanoparticle comprised of a materialother than the therapeutic agent itself. The carrier may be biostable orit may be biodegradable.

Microparticles and nanoparticles can be made of any biocompatiblematerial including, but not limited to a natural, semi-synthetic orsynthetic polymers, ceramics or glasses.

As used herein, “biocompatible” refers to a material that in itsoriginal intact state and when biologically decomposed into itsdegradation products is not toxic or at least is minimally toxic toliving tissue. A biocompatible material does not, or at least minimallyand reparably, injure living tissue. Further, a biocompatible materialdoes not, or at least minimally and controllably, cause an immunologicalreaction in living tissue.

By “biostable” is meant that the material of which the vehicle iscomprised does not appreciably decompose in a physiological environment,for example, without limitation, at physiological pHs or in the presenceof enzymes.

Among useful biocompatible, relatively biostable polymers are, withoutlimitation, polyacrylates, polymethacrylates, polyureas, polyurethanes,polyolefins, polyvinylhalides, polyvinylidenehalides, polyvinylethers,polyvinylaromatics, polyvinylesters, polyacrylonitriles, alkyd resins,polysiloxanes and epoxy resins.

Biocompatible, biodegradable polymers include naturally-occurringpolymers such as, without limitation, collagen, chitosan, alginate,fibrin, fibrinogen, cellulosics, starches, dextran, dextrin, hyaluronicacid, heparin, glycosaminoglycans, polysaccharides and elastin.

Synthetic biocompatible, biodegradable polymers include, withoutlimitation, polylactic acid, polyglycolic acid, polyethylene glycol,polycaprolactone, polyanhydrides, polyvinyl alcohol andpoly(ester-amides).

As used herein, a synthetic polymer refers to one that is created whollyin the laboratory while a semi-synthetic polymer refers to anaturally-occurring polymer than has been chemically modified in thelaboratory. Examples of synthetic polymers include, without limitation,polyphosphazines, polyphosphoesters, polyphosphoester urethane,polyhydroxyacids, polyhydroxyalkanoates, polyanhydrides, polyesters,polyorthoesters, polyamino acids, polyoxymethylenes, poly(ester-amides)and polyimides.

Blends or random, alternating, block, random block or graft copolymersof the above polymers may also be used and are within the scope of thisinvention.

A biostable particle is one that does not appreciably degrade in aphysiological environment, i.e., it maintains its particulate shape inthe presence of physiological factors such as enzymes and otherbiologically active substances.

According to another embodiment of the present invention, thetherapeutic agent can be in the form of an oil-in-water emulsion, awater-in-oil or a water-in-oil-in-water emulsion.

According to another embodiment of the present invention, the devicecomprises a balloon and the vessel surface is a luminal surface. Theballoon may further comprise a catheter, to the disal end of which theballoon is coupled. In accordance with this embodiment of the invention,the balloon is contacted with the luminal surface by inflation, whereinthe inflated balloon comprises substantially one diameter such that thecomplete outer surface of the balloon is contacted with the luminalsurface. Alternatively, the inflated balloon comprises two or more firstdiameters that define portions of the outer surface of the balloon thatare in contact with the luminal surface and one or more second diametersthat define portions of the outer surface that are not in contact withthe luminal surface, wherein the furthest apart of the two of theportions of the balloon that are in contact with the luminal surfacecontact the surface in the non-afflicted region of the vessel at theperiphery of the afflicted region. At present, it is preferred that thetwo furthest apart portions are at least about 40 mm, more particularlyfrom about 40 mm to about 200 mm, and more particularly still, fromabout 40 mm to about 100 mm, apart.

Where the device according to the present invention comprises a balloon,the delivery interface comprises a coating on the outer surface of theballoon, the coating comprising the therapeutic agent.

In the alternative, rather than or in addition to a coating on an outersurface of a balloon, the balloon may be microporous and the therapeuticagent may be contained in a fluid used to inflate the balloon accordingto methods known in the art.

According other embodiments of the present invention, the deliveryinterface comprises a plurality of micro-needles disposed at an outersurface of a balloon.

According to another embodiment of the present invention where thesurface is a luminal surface, the delivery interface comprises animplantable medical device such as, without limitation, a stent.

According to the present invention, regional treatment of vasculardiseases comprises treatment of, without limitation, atherosclerosis,restenosis, vulnerable plaque and peripheral arterial disease using,again without limitation, therapeutic agents that induce apoptosis ofmacrophages, therapeutic agents that initiate reverse cholesteroltransport and anti-inflammatory therapeutic agents.

In an embodiment of this invention, therapeutic agents that induceapoptosis of macrophages include, but are not limited to,bisphosphonates. Bisphosphonates useful with this invention include, butare not limited to, etidronate, clodronate, tiludronate, pamidronate,dimethyl pamidronate, alendronate, ibandronate, risedronate andzeledronate.

In an embodiment of this invention, therapeutic agents that initiatereverse cholesterol transport include, but are not limited to,apolipoprotein A1 and mimetic peptides thereof.

In an embodiment of this invention, therapeutic agents that areanti-inflammatory agent include, but are not limited to, corticosteroidsand statins.

DETAILED DESCRIPTION Brief Description of the Figures

The figures are provided as examples of certain embodiments of thisinvention to aid in its understanding and are not intended nor are theyto be considered as limiting the scope of the invention in any mannerwhatsoever.

FIG. 1 is a schematic depiction of an embodiment of this inventioninvolving the contact of a circumferentially non-continuous, linearlycontinuous segment of a vessel with a delivery interface of thisinvention.

FIG. 2 is a schematic depiction of an embodiment of this inventioninvolving the contact of a circumferentially non-continuous, linearlynon-continuous segment of a vessel with a delivery interface of thisinvention.

FIG. 3 is a schematic depiction of an embodiment of this inventioninvolving the contact of a circumferentially continuous, linearlycontinuous segment of a vessel with a delivery interface of thisinvention.

FIG. 4 is a schematic depiction of an embodiment of this inventioninvolving the contact of a circumferentially continuous, linearlynon-continuous segment of a vessel with a delivery interface of thisinvention.

FIG. 5 is a schematic depiction of an embodiment of this inventionwherein the delivery interface comprises a balloon having substantiallyone diameter when inflated.

FIG. 6 is a schematic depiction of an embodiment of this inventionwherein the delivery interface comprises a balloon having a firstdiameter that, when the balloon is inflated, contacts the surface of avessel, and a second diameter that, when the balloon is inflated, doesnot contact the surface of the vessel.

FIG. 7 is a schematic depiction of an embodiment of this inventionwherein the delivery interface comprises a plurality of separateballoons.

It is to be understood that the use of the singular herein implies theplural and visa versa unless expressly indicated otherwise. For example,without limitation, when the description is directed to the formulation,administration, encapsulation, etc., of a therapeutic agent, the term“therapeutic agent” means a single therapeutic agent or two or moretherapeutic agents.

DEFINITIONS

As used herein, “therapeutic agent” refers to any substance that, whenadministered in a therapeutically effective amount to a patientsuffering from a disease, has a therapeutic beneficial effect on thehealth and well-being of the patient. A therapeutic beneficial effect onthe health and well-being of a patient includes, but it not limited to:(1) curing the disease; (2) slowing the progress of the disease; (3)causing the disease to retrogress; or, (4) alleviating one or moresymptoms of the disease. As used herein, a therapeutic agent alsoincludes any substance that when administered to a patient, known orsuspected of being particularly susceptible to a disease, in aprophylactically effective amount, has a prophylactic beneficial effecton the health and well-being of the patient. A prophylactic beneficialeffect on the health and well-being of a patient includes, but is notlimited to: (1) preventing or delaying on-set of the disease in thefirst place; (2) maintaining a disease at a retrogressed level once suchlevel has been achieved by a therapeutically effective amount of asubstance, which may be the same as or different from the substance usedin a prophylactically effective amount; or, (3) preventing or delayingrecurrence of the disease after a course of treatment with atherapeutically effective amount of a substance, which may be the sameas or different from the substance used in a prophylactically effectiveamount, has concluded.

As used herein, “treating” refers to the administration of atherapeutically effective amount of a therapeutic agent to a patientknown or suspected to be suffering from a vascular disease. A“therapeutically effective amount” refers to that amount of atherapeutic agent that will have a beneficial affect, which may becurative or palliative, on the health and well-being of the patient withregard to the vascular disease with which the patient is known orsuspected to be afflicted. A therapeutically effective amount may beadministered as a single bolus, as intermittent bolus charges, as short,medium or long term sustained release formulations or as any combinationof these. As used herein, short-term sustained release refers to theadministration of a therapeutically effective amount of a therapeuticagent over a period from about several hours to about 3 days.Medium-term sustained release refers to administration of atherapeutically effective amount of a therapeutic agent over a periodfrom about 3 day to about 14 days and long-term refers to the deliveryof a therapeutically effective amount over any period in excess of about14 days.

As used herein, a “vascular disease” refers to a disease of the vessels,primarily arteries and veins, which transport blood to and from theheart, brain and peripheral organs such as, without limitation, thearms, legs, kidneys and liver. In particular “vascular disease” refersto the coronary arterial system, the carotid arterial system and theperipheral arterial system. The disease that may be treated is any thatis amenable to treatment with a therapeutic agent, either as the soletreatment protocol or as an adjunct to other procedures such as surgicalintervention. The disease may be, without limitation, atherosclerosis,vulnerable plaque, restenosis or peripheral arterial disease.

“Atherosclerosis” refers to the depositing of fatty substances,cholesterol, cellular waste products, calcium and fibrin on the innerlining or intima of an artery. Smooth muscle cell proliferation andlipid accumulation accompany the deposition process. In addition,inflammatory substances that tend to migrate to atherosclerotic regionsof an artery are thought to exacerbate the condition. The result of theaccumulation of substances on the intima is the formation of fibrous(atheromatous) plaques that occlude the lumen of the artery, a processcalled stenosis. When the stenosis becomes severe enough, the bloodsupply to the organ supplied by the particular artery is depletedresulting is strokes, if the afflicted artery is a carotid artery, heartattack if the artery is a coronary artery or loss of organ function ifthe artery is peripheral.

“Restenosis” refers to the re-narrowing or blockage of an artery at ornear the where angioplasty or another surgical procedure was previouslyperformed to remove a stenosis. It is generally due to smooth musclecell proliferation at times accompanied by thrombosis. Prior to theadvent of implantable stents to maintain the patency of vessels openedby angioplasty, restenosis occurred in 40-50% of patients within 3 to 6months of undergoing the procedure. Post-angioplasty restenosis beforestents was due primarily to thrombosis or blood-clotting at the site ofthe procedure. While the use of IIb-IIIa anti-platelet drugs such asabciximab and epifabatide, which are anti-thrombotic, reduced theoccurrence of post-procedure clotting and stents reduced it even further(although stent placement itself can initiate thrombosis), stentplacement sites are also susceptible to restenosis due to abnormaltissue growth at the site of implantation. This form of restenosis tendsalso to occur at 3 to 6 months after stent placement but it is notaffected by the use of anti-clotting drugs. Thus, alternative therapiesare continuously being sought to mitigate, preferably eliminate, thistype of restenosis. Drug eluting stents (DES) which release a variety oftherapeutic agents at the site of stent placement have been in use forsome time. These stents, however, have to date comprised deliveryinterfaces that are less than 40 mm in length and in any event havedelivery interfaces that are not intended, and most often do not,contact the luminal surface of the vessel in which they are implanted atthe non-afflicted region at the periphery of the afflicted region.

“Vulnerable plaque” refers to an atheromatous plaque that has thepotential of causing a thrombotic event and is usually characterized bya very thin wall separating it from the lumen of an artery. The thinnessof the wall renders the plaque susceptible to rupture. When the plaqueruptures, the inner core of usually lipid-rich plaque is exposed toblood, with the potential of causing a potentially fatal thromboticevent through adhesion and activation of platelets and plasma proteinsto components of the exposed plaque.

The phenomenon of “vulnerable plaque” has created new challenges inrecent years for the treatment of heart disease. Unlike occlusiveplaques that impede blood flow, vulnerable plaque develops within thearterial walls, but it often does so without the characteristicsubstantial narrowing of the arterial lumen which produces symptoms. Assuch, conventional methods for detecting heart disease, such as anangiogram, may not detect vulnerable plaque growth into the arterialwall.

The intrinsic histological features that may characterize a vulnerableplaque include increased lipid content, increased macrophage, foam celland T lymphocyte content, and reduced collagen and smooth muscle cell(SMC) content. This fibroatheroma type of vulnerable plaque is oftenreferred to as “soft,” having a large lipid pool of lipoproteinssurrounded by a fibrous cap. The fibrous cap contains mostly collagen,whose reduced concentration combined with macrophage-derived enzymedegradations can cause the fibrous cap of these lesions to rupture underunpredictable circumstances. When ruptured, the lipid core contents,thought to include tissue factor, contact the arterial bloodstream,causing a blood clot to form that can completely block the arteryresulting in an acute coronary syndrome (ACS) event. This type ofatherosclerosis is coined “vulnerable” because of unpredictable tendencyof the plaque to rupture. It is thought that hemodynamic and cardiacforces, which yield circumferential stress, shear stress, and flexionstress, may cause disruption of a fibroatheroma type of vulnerableplaque. These forces may rise as the result of simple movements, such asgetting out of bed in the morning, in addition to in vivo forces relatedto blood flow and the beating of the heart. It is thought that plaquevulnerability in fibroatheroma types is determined primarily by factorswhich include: (1) size and consistency of the lipid core; (2) thicknessof the fibrous cap covering the lipid core; and (3) inflammation andrepair within the fibrous cap.

Peripheral vascular diseases are generally caused by structural changesin blood vessels caused by such conditions as inflammation and tissuedamage. A subset of peripheral vascular disease is peripheral arterydisease (PAD). PAD is a condition that is similar to carotid andcoronary artery disease in that it is caused by the buildup of fattydeposits on the lining or intima of the artery walls. Just as blockageof the carotid artery restricts blood flow to the brain and blockage ofthe coronary artery restricts blood flow to the heart, blockage of theperipheral arteries can lead to restricted blood flow to the kidneys,stomach, arms, legs and feet.

As used herein, an “afflicted region” of a vessel is a region thatexhibits clinical manifestations of disease, such as macroscopicevidence in the form of, without limitation, obvious luminal wallthickening, inflammation, etc. or microscopic evidence in the form of,again without limitation, an accumulation of monocytes, macrophages,neutrophiles, smooth muscle cells, inflammatory cytokines, variouslipoproteins, etc.

As used herein, a “non-afflicted region” of a vessel is a region thatdoes not exhibit a clinical manifestation of the disease and appears ashealthy tissue. “Non-afflicted regions at the periphery of the afflictedregion” refers to healthy tissue at the border between afflicted andnon-afflicted regions.

As used herein, a “device” refers to any manner of apparatus that isused or that may be used to in conjunction with a delivery interface ofthis invention. The device may be transitory, that is, it may be adevice that is inserted into a patient's body for only so long as isnecessary to administer a therapeutic agent to the patient from adelivery interface of the device or it may be an implantable medicaldevice intended to remain in a patient's body for longer than necessaryto deliver the therapeutic agent, possibly for as long as the remaininglifetime of the patient. Intermediate between transitory devices andimplantable medical devices intended to remain in place permanently arebiodegradable implantable medical devices which over time degrade tosubstances that can either be adsorbed into or excreted by the body.

An example, without limitation, of a transitory device is a vascularcatheter. A vascular catheter is a thin, flexible tube with amanipulating means at one end, referred to as the proximal end, whichremains outside the patient's body, and an operative device at or nearthe other end, called the distal end, which is inserted into thepatient's artery or vein. The catheter is often introduced into apatient's vasculature at a point remote from the target site, e.g., intothe femoral artery of the leg where the target is in the vicinity of theheart. The catheter is steered, assisted by a guide wire than extendsthrough a lumen in the flexible tube, to the target site whereupon theguide wire is withdrawn at which time the lumen may be used for theintroduction of fluids, often containing therapeutic agents, to thetarget site.

An “implantable medical device” refers to any type of appliance that istotally or partly introduced, surgically or medically, into a patient'sbody or by medical intervention into a natural orifice, and which isintended to remain there after the procedure. As used herein, patientrefers to either a medical or veterinary patient. As noted above, theduration of implantation may be essentially permanent, i.e., intended toremain in place for the remaining lifespan of the patient; until thedevice biodegrades; or until it is physically removed. Examples ofimplantable medical devices include, without limitation, implantablecardiac pacemakers and defibrillators; leads and electrodes for thepreceding; implantable organ stimulators such as nerve, bladder,sphincter and diaphragm stimulators, cochlear implants; prostheses,self-expandable stents, balloon-expandable stents, stent-grafts, grafts,artificial heart valves and cerebrospinal fluid shunts.

Examples of implantable medical devices are, without limitation, vesselwraps and stents. A vessel wrap is a thin sheet of flexible material,which may be fabric, polymer, metal, etc. that is literally wrappedaround the outside of a vessel and is in contact with the outer surface.The wrap may be solid or it may be formed in virtually any manner ofdesired pattern such as, without limitation, a mesh, a ribbed polymericstructure or an embossed metal sheet.

As used herein, a “stent” refers generally to any device used to holdtissue in place in a patient's body. Particularly useful stents,however, are those used for the maintenance of the patency of a vesselin a patient's body when the vessel is narrowed or closed due todiseases including, without limitation, tumors (in, for example, bileducts, the esophagus, the trachea/bronchi, etc.), benign pancreaticdisease, coronary artery disease, carotid artery disease and peripheralarterial disease such as atherosclerosis, restenosis and vulnerableplaque. A stent can be used in, without limitation, neuro, carotid,coronary, pulmonary, aorta, renal, biliary, iliac, femoral and poplitealarteries as well as other peripheral vasculatures. A stent can be usedin the treatment or prevention of diseases such as, without limitation,thrombosis, restenosis, hemorrhage, vascular dissection or perforation,vascular aneurysm, chronic total occlusion, claudication, anastomoticproliferation, bile duct obstruction and ureter obstruction.

In addition to the above uses, stents, including in particular those ofthis invention, may be employed for the delivery of therapeutic agentsto specific treatment sites in a patient's body. In fact, therapeuticagent delivery may be the sole purpose of the stent or the stent may beprimarily intended for another use such as those discussed above withdrug delivery providing an ancillary benefit. For the purpose of thisinvention a stent would be coated with a layer of material comprisingone or more therapeutic agents, the layer comprising a deliveryinterface of this invention that is at least about 40 mm in length.

As used herein, a “delivery interface” refers to a surface region of adevice of this invention that is capable of providing treatment to anarea of the vessel that is greater than that which is accomplished withlocal delivery interfaces known in the art. That is, the deliveryinterface of this invention provides treatment to area of a vessel thatincludes not only the afflicted region of the vessel but non-afflictedregions at the periphery of the afflicted region. Preferably, whendevice according to the present invention is fully deployed, thedelivery interface is capable of being placed in intimate contact withall or portions of a surface of an at least about 40 mm long segment ofa blood vessel and is further capable of delivering a therapeutic amountof the therapeutic agent onto or into the surface of the segmentwherever it is in intimate contact with the vessel surface, with theproviso that if the device is in contact only with portions of thesurface, two of the contact regions are located at least partially inthe above-mentioned periphery of the afflicted region. At present it ispreferred that such contact regions be at least about 40 mm apart. Sinceblood vessels are essentially tubular, i.e., circular in cross-sectionwith a central lumen defined by an interior surface (the luminalsurface) and an exterior surface (the adventitial surface), a “deliveryinterface” of this invention will be capable of delivering a therapeuticagent to the surface in a variety of configurations including, withoutlimitation, the following: (a) FIG. 1 schematically depicts a segment ofa luminal surface of vessel wall 100 contacted by circumferentiallynon-continuous, linearly continuous surface 300 of delivery interface10, which has been directed to the afflicted site by device 200, whichmay be, without limitation, a catheter, or an adventitial surface ofvessel wall 100 contacted by circumferentially non-continuous, linearlycontinuous surface 305 of delivery interface 10; (b) FIG. 2schematically depicts a segment of a luminal surface of vessel wall 100contacted by circumferentially non-continuous, lineally non-continuoussurfaces 310 of delivery interface 10 which has been directed to theafflicted site by device 200, which may be, without limitation, acatheter, or an adventitial surface of vessel 100 contacted bycircumferentially non-continuous, lineally non-continuous surfaces 315of delivery interface 10; (c) FIG. 3 schematically depicts a segment ofa luminal surface of vessel wall 100 contacted by circumferentiallycontinuous, linearly continuous surface 320 of delivery interface 10,which may be directed to the afflicted site by device 200, which can be,without limitation, a catheter, or an adventitial surface of vessel wall100 contacted by circumferentially continuous, linearly continuoussurface 325 of delivery interface 200; or, (d) FIG. 4 schematicallydepicts a segment of a luminal surface of vessel 100 contacted bycircumferentially continuous, linearly non-continuous surface 330 ofdelivery interface 10, wherein the delivery interface may be directed tothe afflicted site by device 200, which can be, without limitation, acatheter, or an adventitial surface of vessel 100 contacted bycircumferentially continuous, linearly non-continuous surface 335 ofdelivery interface 10. It is presently preferred that the total lengthof delivery interface 10 be at least about 40 mm, more particularly fromabout 40 mm to about 200 mm and more particularly still, from about 40mm to about 100 mm in length.

The segment with which the delivery interface is in contact may beafflicted with or suspected to be afflicted with the vascular diseasebeing treated over the entire length of the contact between the surfaceof the delivery interface or only in certain regions of the segment. Forexample, although a delivery interface may be 40 mm in length, onlyisolated regions much less than 40 mm, e.g., as few as one or tworegions that may each be as small as less than about 1 mm or greaterthan 1 mm but less than 40 mm, over the 40 mm interface, may actually beafflicted with the vascular disease. An important aspect of thisinvention, however, is that the delivery interface fully encompasses allregions of the vessel that are so afflicted and, in addition,encompasses a portion of a non-afflicted region at the periphery of theafflicted region. For example, without limitation, in a vessel havingfour regions afflicted or suspected to be afflicted with a vasculardisease, where the most distant of the four regions are 60 mm apart, thedelivery interface of this invention would be at least about 61 or 62 mmand presently preferably from about 65 mm to about 70 mm in length tofully encompass the afflicted region and a portion of the non-afflictedregion at the periphery of the afflicted region.

As used herein, “contacting” a delivery interface with a surface refersto placing the delivery interface surface in contact with the luminal oradventitial surface a vessel along a regional segment of the vessel,preferably an at least about 40 mm long segment of the vessel, such thata therapeutic agent may be transferred from the delivery interfacedirectly onto or into the surface of the vessel. By “onto the surface ofthe vessel” is meant that the therapeutic agent is simply released fromthe surface of the delivery interface and, since the surface of thedelivery interface is in contact with the outer surface of the vessel,the therapeutic agent is also in contact with the outer surface, i.e.,it has been delivered onto the surface of the vessel. By “into thesurface of the vessel” is meant that the delivery interface includessome means such as, without limitation, micro-needles that, when thesurface of the delivery interface is in contact with the surface of thevessel, penetrate the surface of the vessel and deliver the therapeuticagent into the interior of the wall of the vessel.

As used herein, “known” to be afflicted with a vascular disease refersfirst to a condition that is relatively readily observable and ordiagnosable. An example, without limitation, of such a disease isatherosclerosis, which is a discrete narrowing of a patient's arteries.Restenosis, on the other hand, while in its latter stages, likeatherosclerosis, is relatively readily diagnosable or directlyobservable, may not be so in its nascent stage. Thus, a patient may be“suspected” of being afflicted or of being susceptible to afflictionwith restenosis at some time subsequent to a surgical procedure to treatan atherosclerotic lesion. Further, while restenosis tends generally tooccur at the same locus as a previous atherosclerosis, it may not beexactly so, so a region of a segment of a vessel somewhat distant fromthe site of the initial atherosclerosis may in fact be the site of arestenosis.

Vulnerable plaque on the other hand is quite different from eitheratherosclerosis or restenosis and would generally come under thedesignation “suspected” affliction. This is because vulnerable plaqueoccurs primarily within the wall of a vessel and does not causeprominent protrusions into the lumen of the vessel. It is often notuntil it is “too late,” i.e., until after a vulnerable plaque has brokenand released its components into the vessel that its presence is evenknown. Numerous methods have and are being investigated for the earlydiagnosis of vulnerable plaque but to date none have proven completelysuccessful. Thus, the regional treatment of a segment of a vesselsuspected of being afflicted with vulnerable plaque may be the best wayto address such lesions.

As use herein, “delivering a therapeutic agent” refers to the transferof the therapeutic agent from the delivery interface onto or into asurface of a vessel being treated. The transfer may be passive, as inthe case, without limitation, of simple diffusion along a concentrationgradient or it may be active such as when using, again withoutlimitation, the aforementioned micro-needles through which a therapeuticagent is forceably injected into the surface or surroundingperiadventitial space of a vessel.

As used herein, a “vessel wrap” refers to length of flexible material,which may be, without limitation, a fabric, a polymer, a metal and thelike. The length is such that the wrap encompasses not only theafflicted region of a vessel being treated but a portion of thenon-afflicted region at the periphery of the afflicted region. It ispresently preferred that a vessel wrap have a length of at least about40 mm, preferably from about 40 mm to about 200 mm and presently mostpreferably from about 40 mm to about 100 mm. The material is simplywrapped around the adventitial surface of a vessel such that a surfaceof the wrap is in intimate contact with the surface of the vessel overthe entire region of the vessel known or suspected to be afflicted witha vascular disease. A therapeutic agent may be carried on the surface ofthe wrap, either as such or as a pharmaceutically acceptable compositionor it may be located within the wrap substance, again, as such or as apharmaceutical composition.

As used herein, a “balloon” refers to the well-known in the art device,usually associated with a vascular catheter, that comprises a relativelythin, elastomeric material that when positioned at a particular locationin a patient's vessel can be expanded or inflated to an outside diameterthat is essentially the same as the inside or luminal diameter of thevessel in which it is placed. The difference between the normal balloonas currently understood in the art is that the balloon of this inventionachieves the diameter necessary to place it in contact with the luminalsurface of the vessel over an area of the vessel that includes not onlythe afflicted region of the vessel but a portion of the non-afflictedregion at the periphery of the afflicted region. It is presentlypreferred that a balloon of this invention span at least about a 40 mm,more particularly from about 40 mm to about 200 mm and more particularlystill about 40 mm to about 100 mm. segment of the vessel.

Inflation of the balloon may be effected by any means known or as shallbecome known in the art. At present, a balloon of this invention may beinflated using a liquid medium such as water or normal saline solution,that is, saline that is essentially isotonic with blood.

A balloon of this invention may have substantially a single diameterover its entire length such that the full length of the balloon is incontact with the luminal surface of the vessel, as shown in FIG. 5. FIG.5 also shows what is meant by “substantially” a single diameter. As canbe seen in the figure, the ends 550 of balloon 520 are not necessarilysquare so that the balloon does have a large number of diminishingdiameters at the ends at it curves down to join the catheter tube butthe major portion of balloon length 500, which comprises deliveryinterface 10, has substantially the same diameter.

A balloon of this invention may also comprise two different outsidediameters. At each end of the balloon is a first diameter, which is thesame as the diameter of the single diameter balloon described above; thetwo first diameters being sufficiently separated so as to contactnon-afflicted portions of the vessel to either side of the afflictedportion. It is presently preferred that the two first diameters be atleast about 40 mm, more particularly from about 40 mm to about 200 mmand, more particularly still, from about 40 mm to about 100 mm, apart.Between the end first diameters may be any number of additional firstdiameters. Each such first diameter is separated from each other suchdiameter by a second diameter which is less than the inside diameter ofthe vessel and therefore does not contact the luminal surface. Ofcourse, use of the term “a second diameter” is nominal; the point isthat there are regions between the first diameters that are not incontact with the luminal surface and the diameters of those regions maybe identical or all may be different; for the purposes of thisdiscussion it is assumed that they are all the same. This is illustratedin FIG. 6 wherein balloon 620 has first diameters 600, which contactvessel wall 100 and second diameters 650. which do not contact withvessel wall 100 and delivery interface 10 comprises the total length ofthe balloon including both diameters 600 and 650. The balloon isdelivered to the selected site in the vessel by device 400, which maybe, without limitation, a catheter. Depending on the design of thedelivery interface, a therapeutic agent may be delivered only from thosediameters that are substantially the same as the luminal diameter, thesecond diameters acting as spacers only. It is an aspect of thisinvention that therapeutic agent may be delivered directly to a luminalsurface by those surfaces of the delivery interface in contact with theluminal surface; however, it is also an aspect of this invention thatthe therapeutic agent may as well be delivered in to the space betweenthose surfaces; that is, from the surfaces comprising the spacerdiameters. This is discussed in more detail below.

In addition to the single diameter and dual diameter balloons, it isalso an aspect of this invention to use multiple balloons each of whichhas substantially one diameter that is substantially the same as theluminal diameter of the vessel. The end two separate balloons mustcontact the luminal wall at non-afflicted portions of the vessel toeither side of the afflicted portion. As above, it is presentlypreferred that the two balloon be at least about 40 mm, moreparticularly from about 40 mm to about 200 mm and, more particularlystill, from about 140 mm to about 100 mm apart. Such an arrangement ofballoons is illustrated in FIG. 7 where balloons 700, each of which hasthe same diameter, comprise delivery interface 10 and each balloon isattached separated to device 400, which may be, without limitation, acatheter.

A balloon of this invention may comprise a coating on all or part of itssurface, the coating being the delivery interface of this invention.Coated balloons are well-known in the art for the localized delivery oftherapeutic agents and any coating construct known or as may in thefuture become known may be used in the method of this invention with theproviso that at least two contact delivery regions of the balloon mustbe capable of contacting the luminal surface of the vessel in thenon-afflicted region of the vessel at the periphery of the afflictedregion.

Rather than or in addition to being coated, a balloon of this inventionmay be microporous. A microporous balloon comprises a thin membrane inwhich a large number; e.g., hundreds, thousands even millions of holesof substantially uniform size have been created. The holes can range insize from tens of nanometers to microns and can be created by a numberof techniques including, but not limited to, laser drilling and abinitio synthesis. In the latter case, the membrane is synthesized frommolecules that assemble in such a manner than voids are left in thestructure formed. A microporous balloon formed by these or any otherprocedure may be used in the method of this invention.

When using a microporous balloon, the therapeutic agent or agents aredelivered to the balloon at the distal end of a catheter in the fluidused to expand the balloon. When the balloon is expanded, rather thansimply leaking out of the balloon in an uncontrolled manner, the size ofthe holes results in a slow, controlled “weeping” of fluid from theholes and carried along with the fluid are the therapeutic agents. Thefluid and therapeutic agents then spread out over the surface of theballoon in a thin film and when the surface of the balloon is contactedwith the luminal surface of a vessel, the therapeutic agents are broughtinto contact with the luminal surface and held there until theypenetrate the surface of the vessel wall. If a balloon having twodiameters as discussed above is used, only those portions of the balloonhaving the first diameter, that is, the portions that are in contactwith the luminal surface can be microporous with the regionscharacterized by the second diameter are non-porous. In this case,therapeutic agent will be delivered to the luminal surface only by thoseregions of the balloon that are in contact with it. It is also an aspectof this invention, however, that one or more of the regions of theballoon having the second diameter can also be microporous in which casetherapeutic agents will be delivered into the arterial lumen and notdirectly onto the luminal surface.

In another aspect of this invention, the balloon comprisesmicro-needles. Micro-needles, as the name implies, are exceeding smallneedles, often a millimeter or less in length and less than 150 micronsin diameter. The micro-needles may be constructed of permanent materialssuch as stainless steel or they may be constructed of biodegradablepolymers that exhibit thread-forming properties such that they might beattached to an implantable medical device which is left in place butfrom which the micro-needles eventually biodegrade and their degradationproducts are either adsorbed or excreted. One or a large pluralitynumbering in the hundreds, thousands or even more, of thesemicro-needles can be coupled to the surface of a balloon such that, whenthe balloon is deflated, the needles lie substantially parallel to thesurface of the catheter tube to which they and the balloon are attached.As the balloon is being inflated the needles splay out to substantiallyright angles to the surface of the expanding balloon and then, when theballoon approaches a vessel surface, they are forced through the outersurface into the interior of the vessel wall. Therapeutic agents maythen be injected directly into the subsurface tissues and cells of thevessel. This can have a distinct advantage when delivering therapeuticagents to luminal wall of an artery. The inner surface of arteriescomprises a layer of cells called the endothelium. The endothelium is asmooth, slippery surface designed to facilitate blood flow through thearteries. As a result, it can be difficult to get therapeutic agentspast the endothelium to the underlying cells. When the endothelium ispenetrated by the micro-needles, the protective outer surface of thearterial lumen is effectively by-passed and the therapeutic agent can bedelivered directly into the adventia, a layer of fat and elastic fibersthat surrounds and protects the artery. Compared to the endothelium, theadventitia is very receptive to therapeutic agents, which thenrelatively easily permeates and surrounds the cells in the vicinity ofthe injection.

As used herein, a “therapeutic agent” refers to a substance that, whenadministered to a patient has a beneficial effect on the health andwell-being of the patient. Therapeutic agents may be, withoutlimitation, small molecule drugs, large molecule drugs, peptides,antibodies, proteins, enzymes, oligonucleotides, DNAs or RNAs.Representative therapeutic agents for use with the method hereof includebut are not limited to anti-inflammatory compounds, cytostaticcompounds, cytokine inhibiting compounds, growth factor inhibitingcompounds, enzyme inhibiting compounds, signaling pathway inhibitingcompounds and cytotoxic compounds.

A presently preferred therapeutic agent for use in the method of thisinvention is apolipoprotein A1 (apoA1), apoA1 mutants such as, withoutlimitation, apoA1-milano or apoA1 mimetics such as, again withoutlimitation, amphipathic helical peptides. ApoA1 is synthesized in theliver and small intestine and is the primary protein constituent of highdensity lipoprotein (HDL), making up 70% of the latter. ApoA1 isresponsible for most of HDL's defining characteristics including itsparticipation in reverse cholesterol transport. That is, apoA1 definesthe size and shape of the HDL molecule: discoid in its nascent stage,consisting of a phosphatidylcholine bilayer and a protein shell thatshields the hydrophobic lipid tails from the aqueous environment, andspherical in its mature form, consisting of a hydrophobic core ofcholesterol esters shielded by a combination of lipid and protein. Whenmature, HDLs cease to collect cholesterol and are recognized by theliver for excretion. ApoA1 is also responsible for solubilizing of HDL'slipid components, removing cholesterol from peripheral cells, activatinglecithin-cholesterol acyl transferase (LCAT) enzyme and delivering theresulting cholesterol esters to the liver.

Cholesterol is a major component of atherosclerotic plaque. Cholesterolaccumulates in the arterial wall as the result of the influx oflipoproteins containing apoB. When influx exceeds natural efflux,artherosclerotic plaque begins to form. Reverse cholesterol transportrefers to the active efflux and transportation to the liver forexcretion of cholesterol from arterial walls to counter the influx fromthe apoB-containing lipoproteins. While increased levels of HDL havebeen known for some time to correlate with a decreased risk ofatherosclerosis, it has recently been demonstrated that purified apoA1is capable of reducing free cholesterol accumulation in vivo inatherosclerotic lesions. (Boisvert, W. A., et al., Arteriosclerosis,Thrombosis, and Vascular Biology, 1999, 19:525-530). Thus, vessels knownor suspected to be either accumulating cholesterol as the result ofinflux exceeding efflux or to actually be afflicted with atheroscleroticlesions as the result of such accumulation should benefit from theregional administration of apoA1 using the method of this invention.

ApoA1 is a relatively large protein consisting of 243 amino acids. Theproblems associated with working with such large proteins in terms ofstability, bioavailability, etc. are well-known. It would be preferableto use apoA1 mimetic peptides having substantially less amino acids. Onesuch apoA1 mimetic peptide has been reported, an 18-mer that has beenshown to promote reverse cholesterol transport in culturedcholesterol-laden fibroblasts and macrophages and to interact with cellsurface HDL binding sites thereby stimulating an HDL-like response.Mendez, A. J., et al, J. Clin. Invest., 1994, 94:1698-1705. Other suchapoA1 mimetics are being actively sought (see for instance, Mishra, V.K., Biochemistry, 1998, 37:10313-324) and any such compounds discoveredwould be expected to provide a beneficial effect as a therapeutic agentadministered regionally by means of a delivery interface of thisinvention.

A presently preferred family of therapeutic agents useful in the methodof this invention is the bisphosphonates. Bisphosphonates are known toinduce apoptosis in macrophages. Apoptosis is best described as a sortof cell suicide whereby specialized cellular machinery already presentin the cell but previously quiescent is activated, causing the cell todisintegrate into fragments that are then eliminated from the organismcontaining the cell. Macrophages are phagocytotic tissue cells of thereticuloendothelial system that ingest, by engulfing or “cytosing,”foreign substances such as bacteria, cellular debris, viruses, toxins,particulates, etc. Thus macrophages are important to the health andwell-being of humans, With regard to the above-described increasedinflux of cholesterol into the arterial wall, however, which isaccompanied by an increased influx of monocytes/macrophages (monocytesdifferentiate into macrophages) that take up oxidized and aggregated lowdensity lipoprotein (LDL) and store the cholesterol as esters,macrophages perform a disservice to the system. That is, whereasparenchymal cells maintain cholesterol balance by down-regulating denovo cholesterol synthesis and LDL receptor expression, macrophagescontinue to take up cholesterol from apoB-containing lipoproteins bypathways that are not subject to sterol-mediated feedback control.Spady, Circulation, 1999, 576-78. In addition to accumulatingcholesterol, macrophages play a role in inducing plaque rupture, bloodcoagulation and fibrinolysis through the production of various enzymes,activators, inhibitors and therapeutic mediators. Takahashi, et al.,Med. Electron Microsc., 2002, 35(4):179-203. Thus, in the context ofvascular disease, the presence of macrophages is undesirable and theirelimination from vessels known or suspected to be accumulatingcholesterol and therefore to likely be pre-atherosclerotic or in vesselsthat in fact contain atherosclerotic lesions by regional delivery ofbisphosphonates should be of benefit to patients so afflicted.

Bisphosphonates have the general structure:

Bisphosphonates useful in the method of this invention include, but arenot limited to, etidronate (R¹=OH, R²=CH₃), chlodronate (R¹=R²=Cl),tiludronate (R¹=OH, R²=4-chlorophenylmercapto), pamidronate (R¹=OH,R²=2-aminoethyl), olpadronate (dimethyl pamidronate, R¹=OH,R²=N,N-dimethyl-2-aminoethyl), alendronate (R¹=OH, R²=3-aminopropyl),ibandronate (R¹=OH, R²=N-methyl, N-ethyl-2-aminoethyl), risedronate(R¹=OH, R²=3-pyridinylmethyl), minodronate (R¹=OH,R²=4-azaindole-3-methyl) and zoledronate (R¹=OH, R²=1-imidazolylmethyl).

While for some time considered to be simply a lipid storage disease,recent studies have demonstrated that atherosclerosis actually involvesan on-going inflammatory response. In fact inflammation has beenestablished as having a fundamental role in mediating virtually allstages of the disease from initiation through progression and ultimatelyto the thrombotic complications associated with atherosclerosis. Forexample, blood leukocytes, mediators of host defenses and inflammation,have been shown to localize in the earliest lesions of atherosclerosis.The normal endothelium does not in general support binding of whiteblood cells but in the early stages of atherosclerosis patches ofarterial endothelial cells have been observed to express on theirsurface selective adhesion molecules that bind to various classes ofleukocytes. In particular expression of vascular cell adhesionsmolecule-1 (VCAM-1) has been observed on endothelial cells overlyingnascent atheroma. VCAM-1 binds both monocytes (macrophage precursors)and T lymphocytes, both of which are involved in inflammatory responses.Libby, et al., Circulation, 2002, 105:1135. Thus, another presentlypreferred family of therapeutic agents for use in the method of thisinvention are the anti-inflammatory agents. Anti-inflammatory agentsuseful herein include, but are not limited to, statins, corticosteroids,and antioxidants.

A presently preferred class of anti-inflammatory agents for use in themethod of this invention is the statins. Statins are of particularinterest because of their potential dual role in the treatment ofatherosclerosis. That is, the primary function for which they aregenerally prescribed is to lower the production of cholesterol by theliver by blocking the enzyme 3-hydroxy-3-methylglutaryl-coenzyme Areductase (HMG-CoA reductase) A. As noted above, cholesterol plays a keyrole in the formation of atherosclerotic lesions so a reduction in itsproduction should be a major benefit to patients susceptible to orafflicted with atherosclerosis. The results of many clinical studies,however, have shown the improvement in cardiovascular risk reductionobtained from the administration of statins to be superior to theestimations calculated from the effect on LDL cholesterol lowering.Recent studies have shown that statins have an inhibitory effect on themonocyte-endothelial interaction discussed above suggesting ananti-inflammatory effect as well as a cholesterol lowering effect. Thusthe statins should have a marked beneficial effect when administeredregionally using the method of this invention. Useful statins include,but are not limited to, atorvastatin (Lipitor®), lovastatin (Mevacor®),simvastatin (Zocor®), fluvastatin (Lescol®) and pravastatin(Pravachol®).

Another class of presently preferred therapeutic agents for use in themethod of this invention is the corticosteroids. Corticosteroids includecortisol, an adrenal hormone found naturally in the body, as well assynthetic drugs. They all are potent anti-inflammatory compounds withthe synthetic corticosteroids exerting the strongest effects.Corticosteroids potentially useful in the method of this inventioninclude, but are not limited to, alclometasone, amcinonide,betamethasone, clobestasole, clocortalone, desonide, desoxymetasone,diflorasone, fluocinolone, fluocinonide, flurandrenolide, fluticasone,halcinonide, halobetasol, hydrocortisone, methylprednisolone,mometasoneprednicarbate, triamcinolone. Presently particularly preferredcorticosteroids for use herein are clobestesol and desoxymetasone.

Additional therapeutic agents that are presently preferred for use inthe method of this invention are rapamycin and its analogs, sirolimus,biolimus, everolimus, paclitaxel and17-allylamino-17-demethoxygelanamycin (17-AAG).

Of course, a host of other therapeutic agents may be incorporated intothe method of this invention as their use is developed, expanded andfound to be applicable to the diseases and disorders treatable usingregional delivery. Such therapeutic agents include, without limitation,synthetic inorganic and organic compounds, proteins and peptides,polysaccharides and other sugars, lipids, DNA and RNA nucleic acidsequences including siRNA, antisense oligonucleotides, antibodies,receptor ligands, enzymes, adhesion peptides, blood clot agents such asstreptokinase and tissue plasminogen activator, antigens, hormones,growth factors, ribozymes, retroviral vectors, anti-proliferative agentssuch as rapamycin (sirolimus), 40-O-(2-hydroxyethyl)rapamycin(everolimus), 40-O-(3-hydroxypropyl)rapamycin,40-O-(2-hydroxyethyoxy)ethylrapamycin, 40-O-tetrazolylrapamycin(zotarolimus, ABT-578), paclitaxel, docetaxel, methotrexate,azathioprine, vincristine, vinblastine, fluorouracil, doxorubicinhydrochloride, mitomycin, antiplatelet compounds, anticoagulants,antifibrin, antithrombins such as sodium heparin, low molecular weightheparins, heparinoids, hirudin, argatroban, forskolin, vapiprost,curcumin, fingolimandod (FTY-720), prostacyclin, prostacyclin analogues,dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin),dipyridamole, glycoprotein IIb/IIIa platelet membrane receptorantagonist antibody, recombinant hirudin, thrombin inhibitors such asAngiomax ä, calcium channel blockers such as nifedipine, colchicine,fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fattyacid), histamine antagonists, lovastatin, monoclonal antibodies,nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors,suramin, serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine, nitric oxide or nitric oxide donors, super oxidedismutases, super oxide dismutase mimetic, estradiol, anticancer agents,dietary supplements such as vitamins, anti-inflammatory agents such asaspirin, tacrolimus, dexamethasone and clobetasol, cytostatic substancessuch as angiopeptin, angiotensin converting enzyme inhibitors such ascaptopril, cilazapril or lisinopril, antiallergic agents is permirolastpotassium, alpha-interferon, bioactive RGD, and genetically engineeredepithelial cells.

Activation of immune cells and unregulated proliferation and motility ofvascular smooth muscle cells are known to contribute to neointimallesion development during the pathogenesis of atherosclerosis andrestenosis. Vascular smooth muscle cells migrate from thesub-endothelium into the arterial wall intimal layer where theyproliferate and lay down an extracellular matrix that causes vascularwall thickening and reduced vessel patency. Thus, inhibition of thisprocess would be expected then to have a salutary effect in a vesselafflicted with or suspected to be afflicted with actual or nascentatherosclerotic or restenotic lesion(s). Rapamycin, also known assirolimus, is a macrolide compound which has been shown to haveantiproliferative activity toward smooth muscle cells and to inhibitneointimal formation. Thus sirolimus would be expected to be abeneficial therapeutic agent for use with the method of this invention.

Everolimus, (40-O-2-hydroxyethylrapamycin), has, however, has betterpharmacokinetics that sirolimus; i.e., a shorter half-life, a higherbioavailability and a stronger correlation between bioavailability andadministered dose. Thus, while structurally similar, everolimus ispresently preferred over sirolimus for use in the method of thisinvention.

Geldanamycin, a benzoquinone ansamycin isolated from Streptomyceshygroscopicus in the early 1970s, has developed into a promisingchemotherapeutic with activity against a number of cancers. One of itsanalogs, 17-allylamino-17-desmethoxygeldanamycin (17-AAG) is more stableand less toxic than the parent compound and appears to be an equallypotent chemotherapeutic. Both geldanamycin and 17-AAG bind to heat shockprotein 90 (Hsp90) and alter its function. Hsp90 plays a key role inregulating the physiology of cells exposed to environmental stress andin maintaining the malignant phenotype of tumor cells. In addition,Hsp90 participates in the regulation of the cell cycle, cell growth,cell survival and apoptosis. Geldanamycin and 17-AAG bind to theATP-binding pocket of Hsp-90 and induce degradation of proteins thatrequire this chaperone for conformational maturation. More recently,17-MG has been shown to be selectively anti-proliferative toward smoothmuscle cells and not endothelial cells and is being investigated as apotential inhibitor of restenosis and therefore would be expected tohave a beneficial effect in patients being treated using the methodherein.

The therapeutic agent herein may be provided simply as particles or afilm of the agent adhered to the surface of the delivery interface. Orit may be provided as a solution or suspension of the agent in apolymeric matrix adhered to the surface of a delivery interface of thisinvention. Or it may be provided as a pharmaceutically acceptablecomposition adhered to the surface of the delivery interface orentrapped in a polymeric matrix adhered to the surface of the deliveryinterface. A “pharmaceutically acceptable composition” refers tocomposition that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the therapeutic agent. In particular, pharmaceuticallyacceptable compositions for use in the methods of this inventioncomprise encapsulation of the therapeutic agent in a pharmaceuticallyacceptable carrier. Examples of pharmaceutically acceptable carriersinclude but are not limited to micelle encapsulated therapeutic agent,liposome encapsulated therapeutic agent, polymerosome encapsulatedtherapeutic agent, therapeutic agent encapsulated in polymeric micro- ornanoparticles, preferably in particles comprising biodegradable orbioerodable polymer, therapeutic agent encapsulated in micro- ornanoparticles comprising porous glass and/or silica, preferably inparticles comprising biodegradable or bioerodable glass and/or silica,therapeutic agent encapsulated in porous metal micro- or nanoparticles,preferably in particles comprising biodegradable or bioerodable metal.water-in-oil emulsions of therapeutic agent, oil-in-water emulsions oftherapeutic agent, water-in-oil-in-water emulsions of therapeutic agentand oil-in-water-in-oil emulsions of therapeutic agent.

An example, without limitation, of a therapeutic agent being providedsimply as a solution and being administered regionally in that form bymeans of a delivery interface of this invention would be the dissolutionof a water-soluble bisphosphonate, a di-sodium or ammonium salt forinstance, in water or isotonic saline and delivery by means of amicroporous balloon as described above. Generally, the therapeutic agentmust be soluble in water or saline for this means of delivery to beuseful because other solvents may have a deleterious effect on thevessel at the point of delivery. Since many, if not most, therapeuticagents are generally poorly soluble in water, the utility of this meansof delivery is somewhat limited.

For therapeutic agents that are minimally water soluble, the means ofadministration may comprise a suspension of the therapeutic agent in apolymeric matrix which is applied to the surface of a device such as,without limitation, a balloon or stent, which will be in contact withthe wall of a vessel. As such the polymer/therapeutic agent layerbecomes the delivery interface of this invention. Any polymer presentlyknown in the art or as such may become known in the future may be usedfor this mode of administration. A few non-limiting examples arepoly(L-lactide), poly(D-lactide), poly(D,L-lactide), poly(meso-lactide),polyglycolide, poly(L-lactide-co-D,L-lactide),poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(meso-lactide-co-glycolide),poly(caprolactone), poly(hydroxyvalerate), poly(hydroxybutyrate),poly(ester amide), poly(ethylene glycol-co-butylene terephthalate)(POLYACTIVE®), polycaprolactone (PCL), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(glycolic acid-cotrimethylenecarbonate), polyphosphoester, polyphosphoester urethane, poly(aminoacids), cyanoacrylates, poly(trimethylene carbonate),poly(iminocarbonate), copoly(ether-esters), polyalkylene oxalates,polyphosphazenes, polyiminocarbonates, polycarbonates, fibrin,fibrinogen, cellulose, starch, collagen, parylene, polyurethane,polyethylene, polyethylene teraphthalate, ethylene vinyl acetate,silicone, polyethylene oxide, poly(ethylene-co-vinyl alcohol),polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers; acrylic polymers and copolymers, vinyl halide polymers andcopolymers, such as polyvinyl chloride; polyvinyl ethers, such aspolyvinyl methyl ether; polyvinylidene halides, such as polyvinylidenefluoride and polyvinylidene chloride; polyacrylonitrile; polyvinylketones; polyvinyl aromatics, such as polystyrene; polyvinyl esters,such as polyvinyl acetate; copolymers of vinyl monomers with each otherand olefins, such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers; polyamides, such as Nylon 66 and polycaprolactam; alkydresins; polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxyresins; rayon; rayon-triacetate; cellulose, cellulose acetate, cellulosebutyrate; cellulose acetate butyrate; cellophane; cellulose nitrate;cellulose propionate; cellulose ethers; and carboxymethyl cellulose andmixtures thereof.

In the alternative, when a therapeutic agent is poorly soluble aneffective pharmaceutically acceptable composition can be a micelle. Amicelle is a spherical colloidal nanoparticle spontaneous formed by manyamphiphilic molecules in an aqueous medium when the Critical MicelleConcentration (CMC) is exceeded. Amphiphilic molecules have two distinctcomponents, differing in their affinity for a solute, most particularlywater. The part of the molecule that has an affinity for water, a polarsolute, is said to be hydrophilic. The part of the molecule that has anaffinity for non-polar solutes such as hydrocarbons is said to behydrophobic. When amphiphilic molecules are placed in water, thehydrophilic moiety seeks to interact with the water while thehydrophobic moiety seeks to avoid the water. To accomplish this, thehydrophilic moiety remains in the water while the hydrophobic moiety isheld above the surface of the water in the air or in a non-polar,non-miscible liquid floating on the water. The presence of this layer ofmolecules at the water's surface disrupts the cohesive energy at thesurface and lowers surface tension. Amphiphilic molecules that have thiseffect are known as “surfactants.” Only so many surfactant molecules canalign as just described at the water/air or water/hydrocarbon interface.When the interface becomes so crowded with surfactant molecules that nomore can fit in, i.e., when the CMC is reached, any remaining surfactantmolecules will form into spheres with the hydrophilic ends of themolecules facing out, that is, in contact with the water forming themicelle corona and with the hydrophobic “tails” facing toward the centerof the of the sphere. Therapeutic agents suspended in the aqueous mediumcan be entrapped and solubilized in the hydrophobic center of micelleswhich can result in an increase in the bioavailability as well asimproving the stability in biological surroundings, improving thepharmacokinetics and possibly decreasing the toxicity of the therapeuticagent. In addition because of their nanoscale size, generally from about5 nm to about 50 nm, micelles have been shown to exhibit spontaneousaccumulation in pathological areas with leaky vasculature and impairedlymphatic drainage, a phenomenon known as the Enhanced Permeability andRetention or EPR effect.

The problem with micelles formed from relatively low molecular weightsurfactants is that their CMC is usually quite high so that the formedmicelles dissociate rather rapidly upon dilution, i.e., the moleculeshead for open places at the surface of the water with the resultingprecipitation of the therapeutic agent. Fortunately, this short-comingcan be avoided by using lipids with a long fatty acid chain or two fattyacid chains, specifically phospholipids and sphingolipids, or polymers,specifically block copolymers to form the micelles.

Polymeric micelles have been prepared that exhibit CMCs as low as 10⁻⁶ M(molar). Thus, they tend to be very stable while at the same timeshowing the same beneficial characteristics as surfactant micelles. Anymicelle-forming polymer presently known in the art or as such may becomeknown in the future may be used in the method of this invention. Sincemicelles are nano-scale particles, they may be administered using theporous balloon discussed above as well as in polymeric matrices.Examples of micelle-forming polymers are, without limitation, methoxypoly(ethylene glycol)-b-poly(ε-caprolactone), conjugates ofpoly(ethylene glycol) with phosphatidylethanolamine, poly(ethyleneglycol)-b-polyesters, poly(ethylene glycol)-b-poly(L-aminoacids),poly(N-vinylpyrrolidone)-bl-poly(orthoesters),poly(N-vinylpyrrolidone)-b-polyanhydrides andpoly(N-vinylpyrrolidone)-b-poly(alkyl acrylates).

In addition to the classical spherical micelles described above,therapeutic agents may be delivered using the methods of this inventionin compositions comprising synthetic worm micelles. Worm micelles, asthe name suggests, are cylindrical in shape rather than spherical. Theyare prepared by varying the weight fraction of the hydrophilic polymerblock to the total block copolymer molecular weight in the hydrophilicpolymer-b-hydrophobic polymer structure discussed above for preparingspherical micelles. Worm micelles have the potential advantage of notonly being bio-inert and stable as are spherical polymeric micelles butalso of being flexible. Polyethylene oxide has been used extensively tocreate worm micelles with a number of hydrophobic polymers such as,without limitation, poly(lactic acid), poly(ε-caprolactone),poly(ethylethylene) and polybutadiene. A representative description ofworm micelle formation, characterization and drug loading can be foundin Kim, Y., et al., Nanotechnology, 2005, 16:S484-S491. The techniquesdescribed there as well an any other that is currently known or maybecome known in the future may be used in the regional delivery methodof this invention. In addition to compositions comprising micelles,therapeutic agents may be present in or on a delivery interface of thisinvention as a composition comprising liposomes.

Phospholipids are molecules that have two primary regions, a hydrophilichead region comprised of a phosphate of an organic molecule and one ormore hydrophobic fatty acid tails. In particular, naturally-occurringphospholipids have a hydrophilic region comprised of choline, glyceroland a phosphate and two hydrophobic regions comprised of fatty acid.When phospholipids are placed in an aqueous environment, the hydrophilicheads come together in a linear configuration with their hydrophobictails aligned essentially parallel to one another. A second line ofmolecules then aligns tail-to-tail with the first line as thehydrophobic tails attempt to avoid the aqueous environment. To achievemaximum avoidance of contact with the aqueous environment, i.e., at theedges of the bilayers, while at the same time minimizing the surfacearea to volume ratio and thereby achieve a minimal energy conformation,the two lines of phospholipids, know as a phospholipid bilayer or alamella, converge into a sphere and in doing so entrap some of theaqueous medium, and whatever may be dissolved or suspended in it, in thecore of the sphere. Examples of phospholipids that may be used to createliposomes are, without limitation,1,2-dimyristroyl-sn-glycero-3-phosphocholine,1,2-dilauroyl-sn-glycero-3-phosphocholine,1,2-distearoyl-sn-glycero-3-phosphocholine,1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine,1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine,1,2-dioleoyl-sn-glycero-3-phosphate monosodium salt,1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-(1-glycerol)]sodium salt,1,2-dimyristoyl-sn-glycero-3-[phospho-L-serine]sodium salt,1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-glutaryl sodium salt and1,1′,2,2′-tetramyristoyl cardiolipin ammonium salt.

Liposomes may be unilamellar, composed of a single bilayer, or they maybe multilamellar, composed of two or more concentric bilayers. Liposomesrange from about 20-100 nm diameter for small unilamellar vesicles(SUVs), about 100-5000 nm for large multilamellar vesicles andultimately to about 100 microns for giant multilamellar vesicles (GMVs).LMVs form spontaneously upon hydration with agitation of dry lipidfilms/cakes which are generally formed by dissolving a lipid in anorganic solvent, coating a vessel wall with the solution and evaporatingthe solvent. Energy is then applied to convert the LMVs to SUVs, LUVs,etc. The energy can be in the form of, without limitation, sonication,high pressure, elevated temperatures and extrusion to provide smallersingle and multi-lamellar vesicles. During this process some of theaqueous medium is entrapped in the vesicle. Generally, however, thefraction of total solute and therefore the amount of therapeutic agententrapped tends to be rather low, typically in the range of a fewpercent. Recently, however, liposome preparation by emulsion templating(Pautot, et al., Langmuir, 2003, 19:2870) has been shown to result inthe entrapment of virtually 100% of aqueous solute. Emulsion templatingcomprises, in brief, the preparation of a water-in-oil emulsionstabilized by a lipid, layering of the emulsion onto an aqueous phase,centrifugation of the water/oil droplets into the water phase andremoval of the oil phase to give a dispersion of unilamellar liposomes.This method can be used to make asymmetric liposomes in which the innerand outer monolayers of the single bilayer contain different lipids. Anyof the preceding techniques as well as any others known in the art or asmay become known in the future may be used as compositions oftherapeutic agents in or on a delivery interface of this invention.Liposomes comprising phospho- and/or sphingolipids may be used todeliver hydrophilic (water-soluble) or precipitated therapeuticcompounds encapsulated within the inner liposomal volume and/or todeliver hydrophobic therapeutic agents dispersed within the hydrophobiccore of the bilayer membrane.

It has been reported that large unilamellar liposomes alone, that is,absent any additional therapeutic agent, when administered in largeamounts intravenously may stimulate reverse cholesterol transport andmay have anti-atherogenic effects similar to that of HDL. Williams, K.J., et al., Arterioscler. Thromb. Vasc. Biol., 2000, 20:1033-39. Whilefurther evaluation is necessary, if such is proven to be the case,administration of large liposomes without added therapeutic agent usingthe delivery interface of this invention may provide a beneficial effecton patients known or suspected to be afflicted with a vascular disease.

The diblock copolymers discussed above with regard to micelle formationcan be further modified to form bilayer structures similar to liposomes.The structures are referred to as polymerosomes. Depending on the lengthand chemical nature of the polymers in the diblock copolymer,polymerosomes can be substantially more robust that liposomes. Inaddition, the ability to control completely the chemical nature of eachblock of the diblock copolymer permits tuning of the polymerosome'scomposition to fit the desired application. For example, membranethickness can be controlled by varying the degree of polymerization ofthe individual blocks. Adjusting the glass transition temperatures ofthe blocks will affect the fluidity and therefore the permeability ofthe membrane. Even the mechanism of release can be modified by alteringthe nature of the polymers.

Polymerosomes can be prepared in the same manner as liposomes. That is,a film of the diblock copolymer can be formed by dissolving thecopolymer in an organic solvent, applying a film of thecopolymer-containing solvent to a vessel surface, removing the solventto leave a film of the copolymer and then hydrating the film. Thisprocedure, however, tends to result is a polydispersion of micelles,worm micelles and vesicles of varying sizes. Polymerosomes can also beprepared by dissolving the diblock copolymer in a solvent and thenadding a poor solvent for one of the blocks, which will result in thespontaneous formation of polymerosomes.

As with liposomes, polymerosomes can be used to encapsulate therapeuticagents by including the therapeutic agent in the water used to rehydratethe copolymer film. Polymerosomes can also be force-loaded byosmotically driving the therapeutic agent into the core of the vesicle.Also as with liposomes, the loading efficiency is generally low.Recently, however, a technique has been reported that providespolymerosomes of relative monodispersivity and high loading efficiency;generation of polymerisomes from double emulsions. Lorenceau, et al.,Langmuir, 2005, 21:9183-86. The technique involves the use ofmicrofluidic technology to generate double emulsions consisting of waterdroplets surrounded by a layer of organic solvent. Thesedroplet-in-a-drop structures are then dispersed in a continuous waterphase. The diblock copolymer is dissolved in the organic solvent andself-assembles into proto-polymerosomes on the concentric interfaces ofthe double emulsion. The actual polymerosomes are formed by completelyevaporating the organic solvent from the shell. By this procedure thesize of the polymerosomes can be finely controlled and, in addition, theability to maintain complete separation of the internal fluids from theexternal fluid throughout the process allows extremely efficientencapsulation. This technique along with any other technique know in theart or as may become known in the future can be used to prepare acomposition of therapeutic agents for use in or on a delivery interfaceof this invention.

In addition to the preceding membrane enclosed shell structures for theencapsulation of therapeutic agents for use with the delivery interfaceof this invention, a therapeutic agent may also be entrapped inwater-in-oil (WO), an oil-in-water (OW), a water-in-oil-in-water (WOW)or an oil-in-water-in-oil (OWO) emulsion.

An emulsion is simply a dispersion of droplets of a liquid in a secondliquid where the liquids are immiscible. Whether a WO or an OW formsfrom a mixture of water and oil depends to some extent on the volumefraction of each phase but more so on the type of surfactant (sometimescalled an emulsifier) used. That is, according to Bancroft's Rule, thephase in which an emulsifier is more soluble will constitute thecontinuous phase. Which phase a particular emulsifier will be moresoluble in is determined by its hydrophilic-lipophilic balance (HLB)number. HLB by definition range from 1-20. Emulsifiers with a low HLB(i.e., one that is more soluble in oil that in water) will tend to givea WO, while emulsifiers with a high HLB will give OWs. Some commonemulsifiers and their HLBs are, without limitation, acetylatedmonoglycerides (1.5), sorbitan trioleate (1.8), polyethyleneglycolmonostearate (3.4), sorbitan monostearate (4.7), soy lecithin (8.0,polyoxyethylene (20) sorbitan 10.5 and sucrose monolaurate (15.0). Manyother surfactants potentially useful for the formation of WOs and OWsare known in the art and any that is pharmaceutically acceptable may beused to prepare composition of therapeutic agents for use with adelivery interface of this invention. For example, the following areemulsifiers listed as GRAS (generally regarded as safe) by the FDA:diacetyl tartaric acid ester of mono- and di-glycerides, glycerolmonostearate, glycerol monooleate, glycerol behenate, lecithin andmonosodium phosphate derivatives of mono and di-glycerides. Still otheremulsifiers include, without limitation, phosphatidyl choline,stearylamine, deoxycholic acid and polyvinyl alcohol.

The lipid phase of an emulsion may comprise any number of hydrophobicmaterials well-known to those skilled in the art. Among these, withoutlimitation, are such substances as isopropyl myristate, soybean oil,garlic oil and coconut oil.

If desired, an emulsion may be stabilized by incorporation of finelydivided inorganic particles of materials such as, without limitation,carbon, silica or clay in the dispersion (called a Pickering emulsion).The particles adsorb to the surface of the droplets of the dispersedphase, thereby discouraging coalescence of droplets and thus stabilizethe emulsion.

If desired, viscosity enhancers such as, without limitation,polyethylene oxide (PEO 50K), hyaluronic acid or polyvinylpyrrolidine

Droplet sizes in emulsions can vary from nano- to macro-scale, i.e.,from about 10 nanometers (nm) to 100 nm (a nanoemulsion), about 100 nm(0.1 micron) to 100 microns (a microemulsions) or from about 100 micronsto as much as 10 mm (a macroemulsion) in diameter. Droplet size can becontrolled by the use of a homogenizer, a device having a very smalltube through which the droplets are forced, the larger ones beingdistorted such that, upon emergence from the tube they can be shakenapart to form smaller droplets. Other techniques and devices arewell-known in the art and may be used to prepare emulsions of anappropriate size for use with the delivery interface of this invention.In general droplets in the submicron diameter range are presentlypreferred although larger droplets may be used if desired.

In addition to WO and OW emulsions, therapeutic agents may be formulatedas WOW or OWO emulsions. WOW/OWO emulsions are also called doubleemulsions because they consist of droplets of one liquid encased in asecond immiscible liquid that in turn is dispersed a third liquid thatis immiscible with the second liquid; e.g., water-in-oil-in-water oroil-in-water-in-oil. Double emulsions can be prepared by a variety ofmixing techniques or by forcing single emulsions through membranes ornozzles. The size distribution of the droplets tends to be quitedispersed which can limit the utility of such emulsions forpharmaceutical applications. Recently, however, microfluidics has beenused to create double emulsions of precisely controlled droplet size.The technique consists of a series of T-junctions through which thevarious liquids are forced. For example, to create a WOW, junctions weredesigned so that the water flowed into a channel through which oil wasflowing where it was pinched off to form a WO. The WO emulsion was thendirected into a second channel through which water was flowing thuscreating the water-in-oil-in-water double emulsion. Utada, A. S., etal., Science, 2005, 308(5721):53741.

In addition to WO, OW, WOW and OWO emulsions, a therapeutic agent foruse with the delivery interface of this invention may comprise acoacervate. Coacervation is a colloidal phenomenon involving theseparation of a colloidal system into two liquid phases. The phase moreconcentrated in colloidal component is the coacervate while the otherphase is the equilibrium solution. When the coacervate is brought incontact with a core material, that is, a material to be encapsulated,the coacervate spontaneously forms a shell around the core materialresulting in the formation of a microcapsule. In general, coacervationinvolves the mixing together under constant agitation of a core material(therapeutic agent) in a liquid in which the core material is not, or isminimally, soluble. A second solvent containing the coating material,which is likewise not soluble in the first liquid is added upon whichthe coating material is deposited around the core material forming ashell. The shell can be “hardened” by various means such as thermaltreatment or desolvation.

While any therapeutic agent useful in the treatment or prevention ofvascular disease may be administered in any one of the precedingencapsulated forms, bisphosphonates are particularly amenable to suchdelivery techniques. This is because it has long been known thatliposomes containing bisphosphonate are readily engulfed by macrophageswhereupon the liposomes are decomposed by resulting in the release ofthe bisphosphonate which then inactivates and/or limits the growth ofthe macrophage (e.g., see Monkkonen, J., et al., J. Drug Target., 2003,11(5):279-86). It has been reported that the critical size range forphagocytosis-induced macrophage activation is about 0.2 to about 10 μm,a range which each of the above-described encapsulation techniques iscapable of achieving. Thus, in addition to liposomes as deliveryvehicles for bisphosphonates to macrophages, each of the othercompositions discussed above should likewise affect the same macrophageactivation with the same result.

As noted previously, as part of their normal function macrophages engulfand destroy solid particulates such as cell debris and the like. Thus,particulate bisphosphonates should be cytosed by macrophages and shouldhave the same effect once in the macrophage as liposome-transportedbisphosphonate. Thus, insoluble particulate bisphosphonates are alsopharmaceutically acceptable compositions for use with the deliveryinterface of this invention. In particular, it has been reported thathigh concentrations of extracellular calcium enhances the potency ofbisphosphonates against macrophage-type cells (Monkennon, J., et al., J.Drug Target., 1994, 2(4):299-308). Bisphosphonates are known calciumscavengers so it is most likely that in the presence of extracellularcalcium the insoluble calcium salt of the bisphosphonate is formed, thusit is presently preferred that the insoluble bisphosphonate compositionfor use herein is a calcium salt, in particular the dicalcium salt.

While the insoluble particle can be a calcium salt of a syntheticbisphosphonate, it is also an aspect of this invention thatnaturally-occurring calcium phosphate minerals can serve as apharmaceutically acceptable composition for use with a deliveryinterface hereof. Such minerals include, without limitation, brushite,octacalcium phosphate, monetite, whitlocktite, tricalcium phosphate andhydroxyapatite. Of these, hydroxyapatite is presently preferred.

It is also possible, and an aspect of this invention, to load liposomeswith insoluble calcium bisphosphonate particles. The technique involvesthe loading of liposomes with calcium ions by any number of known meanssuch as, without limitation, that described in Messersmith, P. B., etal., Chem. Mater., 1998, 10:109-16. There a soluble bisphosphonate thatis capable of crossing the liposomal lamella, for example withoutlimitation, an ammonium salt, is introduced into the system andbisphosphonate anion is transported across the lamella. Once in the coreof the liposome, the soluble bisphosphonate reacts with the calcium ionspresent and precipitates. When the lamella of the liposome is destroyedby a macrophage the calcium bisphosphonate is released and can affectthe macrophage as discussed above.

An advantage of filing a liposome or other encapsulating shell-typecarrier with an insoluble salt of a bioactive such as a bisphosphonateis improved shelf life of the resulting delivery system. That is,micelles, liposomes and to some extent polymerosomes are susceptible toloss of small molecule encapsulated therapeutic agent as it slowly leaksthrough the membrane of the capsule. If the therapeutic agent isprecipitated within the capsule, the precipitate particle size would beexpected to be too large to transgress the membrane or at least largeenough to significantly reduce the rate of leakage.

In addition to actual precipitates, small molecule therapeutic agentswith acidic functionality might also be rendered less likely to leakfrom shell-type carriers by making a salt of the therapeutic agent witha relatively bulky counter-ion. An example of such a counter-ion is,without limitation, an ammonium salt having the chemical structure:

wherein R₁, R₂, R₃ and R₄ may be the same or different and are selectedfrom groups that will provide the requisite bulkiness. Examples of suchgroups include, without limitation, straight or branched chain alkylgroups, in particular at present groups such at t-butyl, optionallysubstituted aralkyl groups (aryl-Y— where aryl refers to a ring or twoor more fused rings having a fully delocalized π-electron system and Yis an alkyl group) wherein the optional substituent increases the bulkof the molecule without adding reactivity, e.g., a straight chain orbranched alkyl group, an optionally substituted alicyclic group (a ringor two or more fused rings that does not contain a fully delocalizedπ-electron system and a polymeric unit such as polyethylene glycol.Other such bulk-enhancing groups will be immediately evident to thoseskilled in the art based on the disclosure herein.

Another approach to limiting loss of a therapeutic agent from ashell-forming carriers would be the use of counter-ions consisting oftwo or more positively charged regions, i.e., having the chemicalstructure:

wherein R₁, R₂ and R₃ have the same meaning as set forth above and M isvirtually any type of separator entity imaginable. For example, withoutlimitation, 4,4′-bismethylenebiphenyl, polyethylene glycol, any alkylene(—Y—, where Y is a straight or branched chain alkyl group),1,4-cyclohexyl, etc. This approach would be expected to particularlyuseful with divalent therapeutic agents such as the bisphosphonatesdiscussed above.

Coacervates of bisphosphonates may also be used as pharmaceuticallyacceptable compositions for regional delivery of a therapeutic agentusing a delivery interface of this invention. While any coacervate knownin the art and that is pharmaceutically acceptable may be used,polycationic biopolymers are presently preferred. A presently preferredpolycationic biopolymer is chitosan.

With regard to any of the above therapeutic agent delivery meansinvolving a shell-type structure or a particle into which a therapeuticagent is imbedded, the therapeutic effect can be enhanced by including atargeting moiety into the carrier system. Such targeting moieties andtechniques are well-known in the art. For example, without limitation,the surface of a carrier could be modified with antibodies to surfacereceptors known to be associated with the disease being treated.Interaction between the antibody and the receptor would result in thecarrier being bound to the surface at the target site permitting releaseof the therapeutic agent over virtually any desired time period.

Of course, small molecule modification of the carrier surface would alsobe effective. For example, without limitation, NHS(N-hydroxysuccinimidyl) esters would be amenable to transesterificationwith hydroxyl-substituted molecules in the target tissue or to amideformation by reaction of protein amine groups in the tissue.

Another targeting approach would be to modify the target site itself.For example, again without limitation, NHS-biotin might be conjugated toamine groups in proteins known to populate the diseased tissue. Thiswould render the tissue in that region particularly adhesive with regardto carriers, the surface of which has been modified with avidin.

Additional targeting techniques and combinations will be apparent tothose skilled in the art based on the disclosure herein; all suchtechniques and combination are within the scope of this invention.

1. A method of treating a vascular disease, comprising: providing adevice having a regional delivery interface comprising a therapeuticagent; contacting the delivery interface with a surface of a segment ofa vessel that is known or suspected to include a region that isafflicted with a vascular disease, wherein: the delivery interfacecontacts the vessel segment surface not only at the known or suspectedafflicted region but at a non-afflicted region at the periphery of theafflicted region as well; and, delivering the therapeutic agent onto orinto the vessel segment surface from the regional delivery interface incontact with the vessel segment surface.
 2. The method of claim 1,wherein the regional delivery interface is about 40 mm or more inlength.
 3. The method of claim 2, wherein the entire length of theregional delivery interface contacts the vessel segment surface.
 4. Themethod of claim 2, wherein two or more segments of the regional deliveryinterface contact the vessel segment surface provided that one or moreof the regional delivery interface segments contact(s) the vesselsegment surface at the afflicted regions and one or more regionaldelivery interface segments contact the vessel segment at thenon-afflicted regions of the vessel segment.
 5. The method of claim 1,wherein the therapeutic agent comprises a pharmaceutically acceptablecomposition.
 6. The method of claim 5, wherein the pharmaceuticallyacceptable composition comprises a micelle, a worm micelle, a liposomeor a polymerosome.
 7. The method of claim 5, wherein thepharmaceutically acceptable composition comprises an oil-in-wateremulsion or a water-in-oil-in-water emulsion.
 8. The method of claim 1wherein the device comprises a self-expanding structure.
 9. The methodof claim 1, wherein the device comprises a balloon and the surface ofthe segment of a vessel is a luminal surface.
 10. The method of claim 9,wherein the device further comprises a catheter.
 11. The method of claim10, wherein the balloon is coupled to a distal end of the catheter. 12.The method of claim 11, wherein an outer surface of the balloon iscontacted with the luminal surface of the vessel segment by inflation ofthe balloon.
 13. The method of claim 12, wherein the inflated ballooncomprises substantially one diameter such that the complete outersurface of the balloon is contacted with the luminal surface.
 14. Themethod of claim 12, wherein the inflated balloon comprises two or morefirst diameters that define portions of the outer surface of the balloonthat are in contact with the luminal surface and one or more seconddiameters that define portions of the outer surface that are not incontact with the luminal surface, wherein: two of the portions of theballoon that are in contact with the luminal surface contact the vesselsurface in non-afflicted regions at the periphery of the afflictedregion.
 15. The method of claim 9, wherein the delivery interfacecomprises a coating on the outer surface of the balloon, the coatingcomprising the therapeutic agent.
 16. The method of claim 9, wherein theballoon is microporous.
 17. The method of claim 16, wherein thetherapeutic agent is contained in a fluid used to inflate the balloon.18. The method of claim 9, wherein the delivery interface comprises aplurality of micro-needles disposed at an outer surface of the balloon.19. The method of claim 1, wherein the device comprises an implantablemedical device and the vessel segment surface is a luminal surface. 20.The method of claim 19, wherein the implantable medical device is astent.
 21. The method of claim 1, wherein the vascular disease isselected from the group consisting of atherosclerosis, restenosis,vulnerable plaque and peripheral arterial disease.
 22. The method ofclaim 1, wherein the therapeutic agent induces apoptosis of macrophagesand/or of foam cells.
 23. The method of claim 22, wherein thetherapeutic agent comprises a bisphosphonate.
 24. The method of claim23, wherein the bisphosphonate is selected from the group consisting ofetidronate, clodronate, tiludronate, pamidronate, dimethyl pamidronate,alendronate, ibandronate, risedronate and zeledronate.
 25. The method ofclaim 23, wherein the bisphosphonate comprises a pharmaceuticallyacceptable composition.
 26. The method of claim 25, wherein thepharmaceutically acceptable composition comprises a micelle, a wormmicelle, a liposome, or a polymerosome.
 27. The method of claim 26,wherein the bisphosphonate is a salt comprising a counter-ion thatreduces leakage of the bisphosphonate from the composition.
 28. Themethod of claim 27, where the counter-ion comprises bulk-enhancinggroups.
 29. The method of claim 27, wherein the counter-ion comprisestwo positively charged species covalently bonded to a linker group. 30.The method of claim 25, wherein the pharmaceutically acceptablecomposition comprises a water-in-oil emulsion or a water-in-oil-in-wateremulsion.
 31. The method of claim 25, wherein the pharmaceuticallyacceptable composition comprises a coacervate of the bisphosphonate 32.The method of claim 31, wherein the coacervate is a polycationicbiopolymer.
 33. The method of claim 32, wherein the polycationicbiopolymer is chitosan.
 34. The method of claim 24, wherein thepharmaceutically acceptable composition comprises a microparticle or ananoparticle.
 35. The method of claim 34, wherein the microparticle ornanoparticle comprises an insoluble salt of the bisphosphonate.
 36. Themethod of claim 35, wherein the insoluble salt is a dicalcium salt. 37.The method of claim 34, wherein the microparticle or nanoparticlecomprises a calcium phosphate mineral.
 38. The method of claim 37,wherein the calcium phosphate mineral is selected from the groupconsisting of brushite, octacalcium phosphate, monetite, whitlocktite,tricalcium phosphate and hydroxyapatite.
 39. The method of claim 38,wherein the calcium phosphate mineral is hydroxyapatite.
 40. The methodof claim 1, wherein the therapeutic agent initiates reverse cholesteroltransport.
 41. The method of claim 40, wherein the therapeutic agent isselected from the group consisting of apolipoprotein A1 andapolipoprotein A1 mimetic peptide.
 42. The method of claim 1, whereinthe therapeutic agent is an anti-inflammatory agent.
 43. The method ofclaim 42, wherein the anti-inflammatory agent is selected from the groupconsisting of corticosteroids and statins.
 44. The method of claim 43,wherein the corticosteroid is selected from the group consisting ofclobetasol and desoxymetasone.
 45. The method of claim 1, wherein thetherapeutic agent comprises everolimus, rapamycin, biolimus, sirolimus,paclitaxel.
 46. The method of claim 1, wherein the therapeutic agentcomprises 17-AAG.
 47. A device, comprising: a regional deliveryinterface wherein: the regional delivery interface comprises atherapeutic agent, wherein: the regional delivery interface contacts asegment of a vessel at one or more regions of the vessel known orsuspected to be afflicted with a vascular disease and one or morenon-afflicted regions of the vessel at the periphery of the afflictedregions.
 48. The device of claim 47, comprising a catheter.
 49. Thedevice of claim 48, wherein the regional delivery interface comprises aballoon coupled to a distal end of the catheter.
 50. The device of claim47, wherein the device comprises an implantable medical device.
 51. Thedevice of claim 50, wherein the implantable medical device comprises astent.